The extensive multidrug resistance (MDR) in cancer cells has been a major obstacle to successful cancer chemotherapy. An important mechanism for MDR is the enhanced cellular efflux of anticancer agents due to over-expression of ATP-binding cassette (ABC) transporter proteins.1 Among the 48 ABC transporters identified so far, P-glycoprotein (P-gp, ABCB1), multidrug resistance protein (MRP1, ABCC1) and breast cancer resistance protein (BCRP, ABCG2) are three main efflux transporters associated with MDR.2 The structures and functions of ABC transporters have been studied extensively by scientists. It is known that all ABC proteins consist of transmembrane domains (TMDs), and nucleotide-binding domains (NBDs).3 P-gp has been identified to possess cytosolic N- and C-termini, two TMDs of 6 helices each, and two NBDs in a single 1280-residue polypeptide.3-6 
The structure of the 1531-residue MRP1 is similar to that of P-gp, but the protein possesses an extra N-terminal TMD with 5 transmembrane (TM) helices, termed TMD0, whose function remains unclear.3,5,7,8 BCRP is a 655-residue half-transporter that possesses an N-terminal NBD and a 6-helix TMD. The functional protein of BCRP is assumed to operate as a homodimer.3,5,9,10 
However, the binding modes and binding sites of these three transporter proteins with their substrates are not clear. There is no common “pharmacophore” that can be used to function as an inhibitor of these three ABC transporters.3 Structurally diverse inhibitors or modulators of ABC multidrug efflux pumps have been identified by homology modeling, combinatorial chemistry, QSAR analysis, and utilization of protein structure information.11-14 There have been three generations of P-gp inhibitors. The first generation P-gp inhibitors include calcium channel blocker verapamil,15-17 antimalarial drug quinidine,18 calmodulin antagonists,19,20 the immunosuppressant cyclosporine A21-24 and some steroids.25-27 The second generation P-gp chemosensitizer include dexverapamil,28 PSC833 (valspodar),26,29 dexniguldipine,30 and VX-710 (biricodar).31,32 
The third generation MDR modulators developed by structure-activity relationships and combinatorial chemistry approaches include zosuquidar LY335979, tariquidar XR9576, laniquidar R101933, elacridar GF120918 and the substituted diarylimidazole ONT-090.33,34 Among them, only a very few were selected for clinical trial and none of them has been approved yet for clinical application.
Fewer MRP1 inhibitors have been identified. Most MRP1 substrates, as well as inhibitors, are anionic compounds that enter cells poorly, thus making it difficult to design a good inhibitor for MRP1 compared to P-gp. The Leukotriene C4 (LTC4) analogue (MK571),3,35 glibenclamide,36 probenecid37 and some non-specific inhibitors of organic anion transporters like NSAIDs (e.g. indomethacin)38,39 have been described as MRP1 modulators. Pantoprazole, fumitremorgin C, and its derivatives Ko132, Ko134 and Ko1433,40 are specific ABCG2 inhibitors. Besides, some third generation P-gp inhibitors such as elacridar41 and tariquidar42 also modulate ABCG2 activity.
Flavonoids are polyphenolic compounds commonly found in fruits, vegetables, and plant-derived products of the human diet.43 Because humans consume large amounts of flavonoids daily, it is generally accepted that flavonoids are not toxic. Moreover, it has been reported that some flavonoids have been found to reverse cancer MDR. Some flavonoids like genistein, chrysin, biochanin, quercetin, kaempferol and naringenin have inhibitory activity on P-gp mediated transport of.44-49 
Other flavonoids like aglycones and glycosides have been shown to inhibit MRP1-mediated transport to various degree.50-52 Many flavonoids have also been shown to interact with BCRP transporter. They significantly inhibit the BCRP-mediated transport of topotecan and mitoxantrone in BCRP-overexpressing cancer cells.53-56 Flavonoids are therefore promising candidates for development of novel modulators of MDR.